Composition

ABSTRACT

There is described a pharmaceutical composition comprising one or more of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol; 5-(2-hydroxy-propoxy)-8-propyl-chromone-2-carboxylic acid; 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid; 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid; or a pharmaceutically acceptable salt of any one thereof, in combination with one or more of aspirin, indomethacin, phenylbutazone or oxyphenbutazone. (Mixtures of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharmaceutically acceptable salt thereof, with aspirin or indomethacin do not form part of the invention). 
     There are also described packages containing the separate components of the composition and pharmaceutical formulations containing the composition.

This is a division of application Ser. No. 863,859, filed Dec. 23, 1977,now U.S. Pat. No. 4,151,292, which latter application is in turn acontinuation-in-part of application Ser. No. 742,750, filed Nov. 18,1976, now U.S. Pat. No. 4,066,756.

This invention relates to a mixture and a method for its preparation.

Aspirin, indomethacin, phenylbutazone, oxyphenbutazone and mixturesthereof (herein referred to collectively as `the anti-inflammatory`),are widely used in the treatment of inflammatory conditions, but sufferfrom the disadvantage that they can cause gastro-intestinal irritation,pain, nausea, indigestion and in particular gastro-intestinal microbleeding. We have now surprisingly found that the gastro-intestinal sideeffects of the anti-inflammatory can be inhibited by the application ofcertain chromone compounds in combination with the anti-inflammatory.

According to our invention therefore we provide a pharmaceuticalcomposition comprising one or more of1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol;5-(2-hydroxypropoxy)-8-propylchromone-2-carboxylic acid;6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylicacid;6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylicacid; or a pharmaceutically acceptable salt of any one thereof, (hereinreferred to collectively as `active ingredient`) in combination with theanti-inflammatory, provided that the composition does not comprise1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharmaceuticallyacceptable salt thereof, in combination with aspirin or indomethacin.

We prefer to use the di-sodium salt of1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, which is commonly known asdisodium cromoglycate, or cromolyn sodium.

We prefer the mixture to contain only one active ingredient and only oneanti-inflammatory.

The ratios of anti-inflammatory to one part by weight of activeingredient (calculated as the mono-sodium salt or, in the case of1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, as the di-sodium salt) areas follows:

    ______________________________________                                        Anti-inflammatory     Active Ingredient                                       (parts by weight)     (one part by weight)                                    ______________________________________                                        (a) Phenylbutazone or oxyphenbutazone                                         2,000 to 0.14        1,3-bis-(2-carboxy-                                      preferably 200 to 0.35                                                                             chromon-5-yloxy)                                         more preferably 200 to 1.4                                                                         propan-2-ol or a                                                              pharmaceutically                                                              acceptable salt thereof                                  (b) Aspirin                                                                   24 to 0.024          5-(2-hydroxypropoxy)                                     preferably 4.0 to 0.12                                                        8-propyl-chromone-2-                                                                               carboxylic acid, or a                                                         pharmaceutically                                                              acceptable salt thereof                                  (c) Indomethacin                                                              4.0 to 0.004         5-(2-hydroxypropoxy                                      preferably 4.0 to 0.01                                                        8-propyl-chromone-2-                                                                               carboxylic acid, or a                                                         pharmaceutically                                                              acceptable salt thereof                                  (d) Phenylbutazone or oxyphenbutazone                                         8.0 to 0.028         5-(2-hydroxypropyl)                                      preferably 8.0 to 0.14                                                        8-propyl-chromone-2-                                                                               carboxylic acid, or a                                                         pharmaceutically                                                              acceptable salt thereof                                  (e) Aspirin                                                                   1200 to 0.3          6,7,8,9-tetrahydro-                                      preferably 1200 to 0.6                                                                             4-oxo-10-propyl-4H-                                                           naphtho[2,3-b]-                                                               pyran-2-carboxylic                                                            acid, or 6,7,8,9-                                                             tetrahydro-5-hydroxy-                                                         4-oxo-10-propyl-4H-                                                           naphtho[2,3-b]                                                                pyran-2-carboxylic                                                            acid or a                                                                     pharmaceutically                                                              acceptable salt                                                               of either thereof                                        (f) Indomethacin                                                              200 to 0.05          6,7,8,9-tetrahydro-                                      preferably 200 to 0.1                                                                              4-oxo-10-propyl-4H-                                                           naphtho [2,3-b,]-                                                             pyran-2-carboxylic                                                            acid, or 6,7,8,9-                                                             tetrahydro-5-hydroxy-                                                         4-oxo-10-propyl-4H-                                                           naphtho[2,3-b]                                                                pyran-2-carboxylic                                                            acid or a                                                                     pharmaceutically                                                              acceptable salt                                                               of either thereof                                        (g) Phenylbutazone or oxyphenbutazone                                         400 to 0.35          6,7,8,9-tetrahydro-                                      preferably 400 to 0.7                                                                              4-oxo-10-propyl-4H-                                                           naphtho[2,3-b]-                                                               pyran-2-carboxylic                                                            acid, or 6,7,8,9-                                                             tetrahydro-5-hydroxy-                                                         4-oxo-10-propyl-4H-                                                           naphtho[2,3-b-]                                                               pyran-2-carboxylic                                                            acid or a                                                                     pharmaceutically                                                              acceptable salt                                                               of either thereof                                        ______________________________________                                    

The daily dosages for humans for most anti-inflammatory purposes of theanti-inflammatories are as follows:

(a) Aspirin 3 to 80, and preferably 3 to 40, mg/kg of the subject to betreated's body weight.

For an adult human 180 mg to 4.8 g, preferably 180 mg to 2.4 g,preferably given in divided doses 3 to 8, and preferably 3 to 4 times aday.

(b) Indomethacin 0.33 to 8.33, and preferably 0.83 to 2.5, mg/kg of thesubject to be treated's body weight.

For an adult human 20 to 500, preferably 50 to 150 mg, preferably givenin divided doses 2 to 5 and preferably 2 to 3 times per day.

(c) Phenylbutazone or Oxyphenbutazone 1.7 to 15, and preferably 3.3 to10, mg/kg of the subject to be treated's body weight.

For an adult human 100 to 900, preferably 200 to 600, mg preferablygiven in divided doses 2 to 3 times per day.

Each dose of the anti-inflammatory may comprise one or more unit doses,e.g. tablets or capsules.

The daily dosages of the active ingredient can, if desired, be obtainedby simple calculation.

For human use compositions in unit dosage form comprise the quantitiesof active ingredient (calculated as the mono-sodium salt and, in thecase of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, as the di-sodiumsalt), and of the anti-inflammatory specified below:

(a) Aspirin 60 to 600 mg, preferably 180 to 600 mg.

(b) Indomethacin 10 to 100 mg, preferably 25 to 50 mg.

(c) Phenylbutazone or oxyphenbutazone 70 to 200 mg, preferably 100 to200 mg.

(d) 1,3-Bis-(2-carboxychromon-5-yloxy)propan-2-ol

0.1 to 500 mg, preferably 1 to 200 mg and more preferably 1 to 50 mg.

(e) 5-(2-Hydroxypropoxy)-8-propyl-chromone-2-carboxylic acid

25 mg to 2.5 g, preferably 25 to 500 mg.

(f)6,7,8,9-Tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylicacid or6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho-[2,3-b]pyran-2-carboxylicacid

0.5 to 200 mg, preferably 0.5 to 100 mg.

According to our invention we also provide a method for the treatment ofan inflammatory and/or painful condition, e.g. arthritis such asrheumatoid arthritis, rheumatism and other disorders, e.g. inflammatorydisorders or platelet aggregation, normally treated with theanti-inflammatory, which comprises administration of a compositionaccording to the invention to an individual mammal, e.g. human,suffering from such a condition. The administration is preferably peros, and is most preferably administration by mouth (oesophagealadministration).

According to the invention we also provide a method for the treatment ofan inflammatory and/or painful condition, e.g. arthritis such asrheumatoid arthritis, rheumatism, and other disorders, e.g. inflammatorydisorders or platelet aggregation, normally treated with theanti-inflammatory, which comprises sequential or simultaneousadministration of active ingredient and the anti-inflammatory (providedthat the administration does not comprise administration of1,3-bis(2-carboxychromon-5-yloxy)-propan-2-ol, or a pharmaceuticallyacceptable salt thereof, and aspirin or indomethacin) to an individualmammal, e.g. human, suffering from such a condition or disorder.

The active ingredient is preferably administered in such a way that itis available in the gastrointestinal tract before the anti-inflammatory,e.g. the active ingredient may be administered before theanti-inflammatory. Alternatively the active ingredient may beadministered together with, or after the anti-inflammatory, but in suchcircumstances the anti-inflammatory is preferably used in delayed orsustained release form.

When sequential or simultaneous administration of active ingredient andthe anti-inflammatory is used the ratios and dosages of the activeingredient and the anti-inflammatory are as described above with respectto the mixtures.

The invention therefore also provides a pharmaceutical packagecomprising at least one unit dose of active ingredient and at least oneunit dose of the anti-inflammatory, provided that the package does notcomprise a unit dose of 1,3-bis(2-carboxychromon-5-yloxy)-propan-2-ol,or a pharmaceutically acceptable salt thereof, and a unit dose ofaspirin or indomethacin. The unit doses are preferably arranged in thepackage in a particular order together with written or printedindications or directions, the indications or directions and the mannerof packing being such as to provide guidance in relation to and tofacilitate the taking of a unit dose of active ingredient and a unitdose of the anti-inflammatory in a particular order, e.g. a unit dose ofthe former before a unit dose of the latter. The package is preferably asealed package and may comprise a tube, box or chart in or on which theunit doses are packed. The unit doses are preferably suitable foroesophageal administration and preferably contain the doses of activeingredient and the anti-inflammatory in the ratios set out above for thecombinations.

The suppression of the side effects of the anti-inflammatory may befurther enhanced by the post- or preferably pre-dosing of the subjectwith additional active ingredient.

In order to produce suitable compositions the active ingredient and theanti-inflammatory, either separately or as a mixture thereof, may bemixed with organic or inorganic pharmaceutically acceptable adjuvants,diluents or excipients. Examples of such adjuvants are:

For tablets and dragees: Binders, for example, cellulosic materials,e.g. microcrystalline cellulose and methyl cellulose; disintegratingagents, for example starches, e.g. maize starch; stabilizers, e.g.against hydrolysis of the active ingredients; flavouring agents, forexample sugars such as lactose; fillers; stearates and inorganicdiluents, e.g. talc.

For syrups, suspensions or dispersions: A liquid vehicle in which theactive ingredients may be dissolved or suspended, e.g. water; andsuspending agents, e.g. cellulose derivatives, gums etc.

For hard or soft capsules: Diluents, e.g. lactose; glidants, e.g.stearates; inorganic materials, e.g. silica or talc; stabilizers anddispersing agents.

For suppositories: Natural or hardened oils, waxes etc. A large numberof proprietary emulsifying bases are available and are suitable for usein suppositories. These include `Witepsol` bases, consisting ofhydrogenated triglycerides of lauric acid with added monoglycerides; and`Massupol` bases, which consist of glyceryl esters of lauric acid with avery small amount of glyceryl monostearate.

For enemas: Water, sodium chloride, buffers etc.

We prefer compositions which are designed to be administered by mouth(oesophageally).

The composition may also contain further adjuvants, for example acomposition for use in tablets may contain lubricants and glidants toassist in tabletting, e.g. magnesium stearate, or wetting agents toassist in granulation, e.g. dioctyl sodium sulphosuccinate. Thecomposition may also if desired contain a pharmaceutically acceptabledye or colourant, and may, if desired, be coated using conventional filmor sugar coating techniques.

If desired the composition, or one or more components thereof, may beformulated in sustained release form, e.g. by coating some or all of thedrug particles themselves or granules thereof made with, for example,sucrose and of a size up to 2 mm in diameter with a layer of, e.g.beeswax, Carnuba wax, stearic or palmitic acids, cetyl alcohol orsimilar substances which could be expected to be slowly dissolved ordigested or to act as semi-permeable membranes through which the drugscan diffuse when the preparations are ingested. The composition maycontain drug particles or granules which are uncoated in admixture withparticles or granules having one or more coats of the coating medium,and may be in the form of a capsule containing the particles or granulesor alternatively a tablet, for which other adjuvants may be required,such as glidants or lubricants. The mixture may be administered as anenteric coated composition to make the drugs available at theappropriate part of the gastro-intestinal tract. This may be achieved bycoating the tablet with a continuous film of material which is resistantand impermeable to gastric secretions, but which is susceptible tointestinal secretions. Typical film materials are shellac and itsderivatives and cellulose acetate phthalate.

We prefer compositions which are adapted to release some or all of theactive ingredient first and to release the anti-inflammatory later. Thusa solid composition may comprise a core of the anti-inflammatorysurrounded in part or in whole by an outer layer containing the activeingredient. The core may, if desired or necessary, be coated with amaterial which is relatively slowly dissolved or degraded by the gastricjuices, e.g. shellac, beeswax, Carnuba wax, stearic or palmitic acids,or cetyl alcohol or the like and this coating may in turn be coated witha material containing the active ingredient which is relatively quicklydissolved or degraded by the gastric juices, e.g. sugar or a celluloseether such as hydroxypropylmethylcellulose. Alternatively thecomposition may comprise discrete particles of the active ingredient,which may be coated or uncoated, but which are adapted to dissolve ordisperse quickly in the gastro-intestinal tract, in admixture withdiscrete particles of the anti-inflammatory which are preferably coatedor treated so that they dissolve or disperse the anti-inflammatoryslowly in the gastrointestinal tract. We prefer the composition to besuch that the anti-inflammatory begins to be available in thegastrointestinal tract from about 5 to 15 minutes after the activeingredient commences to be available in the gastrointestinal tract.

The active ingredient and the anti-inflammatory may, if desired, be usedin a specific form, e.g. having a mass median diameter of less than 10microns.

The active ingredient and the anti-inflammatory may also be formulatedas an aqueous, e.g. a water chloroform (400:1), solution containing from0.001 to 10.0% by weight of the active ingredient plus theanti-inflammatory.

We prefer compositions containing aspirin.

The compositions according to the invention may be made by, e.g. drymixing the active ingredient and the anti-inflammatory optionallytogether with a pharmaceutically acceptable adjuvant, diluent orexcipient, for example in a powder blending machine. The mixing may becarried out in two stages, the blend, or parts thereof, being sievedthrough an appropriate screen (e.g. 60 mesh, 250 micron) at the end of afirst stage in order to disperse any persistant aggregates. The sievedpowder may then be mixed further. The resulting mixture may then, forexample, be compressed in a tablet forming machine or filled into acapsule.

We also provide a process for the production of unit dosage formsaccording to the invention, which comprises forming a mixture of theactive ingredient and the anti-inflammatory, optionally in admixturewith a pharmaceutically acceptable adjuvant, diluent or carrier, intodiscreet and separate units each of which comprises the required unitdosage. The forming into discreet units will normally be effected byfilling an appropriate volume (or weight) of the finely divided orgranulated active ingredient and anti-inflammatory, optionally incombination with an adjuvant, diluent or carrier into a defined space,e.g. a capsule, or the die of a tabletting machine.

The invention is illustrated, but in no way limited by the followingExamples.

EXAMPLE 1

    ______________________________________                                                            mg/tablet                                                 ______________________________________                                        Phenylbutazone or oxyphenbutazone                                                                   100                                                     Disodium cromoglycate 100                                                     Maize starch BP as binder                                                                           15                                                      Maize starch BP as disintegrant                                                                     45                                                      Microcrystalline cellulose BPC                                                                      80                                                      Talc                  10                                                                            350                                                     ______________________________________                                    

EXAMPLE 2 1. Central Core Formulation

Phenylbutazene or oxyphenbutazone 100 mg

Maize Starch BP 45 mg

Sieve the phenylbutazone or oxyphenbutazone through a 20 mesh sieve andthe maize starch through a 40 mesh sieve. Mix these ingredients andcompress into `slugs`. Granulate the `slugs` using a 12 mesh screen.

2. Formulation of Outer Layer

    ______________________________________                                                          mg     % By weight                                          ______________________________________                                        1,3-Bis(2-carboxychromon-5-yloxy)-                                            2-hydroxypropane, disodium salt                                                                   100      49.8                                             Sodium bicarbonate BP                                                                             75       37.3                                             Maize starch BP     17.8     8.9                                              Talc BP (sterilised)                                                                              8.0      4.0                                              Purified water BP   QS       QS                                                                   200.8    100.0                                            ______________________________________                                    

The sodium bicarbonate, after being passed through a 100 mesh screen,was mixed in a drum roller with the bis-chromone, which had been passedthrough a 60 mesh screen. Half the starch was then added, and the drumwas rolled for about 20 minutes. The mixed powder was then transferredto a mixing bowl and dampened down with the water (approximately 120 mlper kg of dry powder). The damped powder was then passed through an 8mesh screen and was dried at 50° C. for 2 hours, the dry product thenbeing passed through a 16 mesh screen and blended with the talc and theremaining starch.

3. Intermediate Layer

An inert intermediate layer may, if desired, be used between the coreand outer layer to delay the onset of disintegration and dissolution ofthe phenylbutazone or oxyphenbutazone containing core. This intermediatelayer may consist of fillers, e.g. lactose, dicalcium phosphate, apolymeric binder e.g. gelatin, polyvinylpyrrolidone, and a lubricante.g. metallic stearates, talc etc. A suitable formulation comprises:

Lactose BP 120 mg

Dicalcium phosphate USP XVII 30 mg

Gelatin BP 3 mg

Magnesium stearate BP 1 mg

The lactose and dicalcium phosphate, after being passed through a 40mesh sieve, were mixed in a planetary mixer for 10 minutes and dampeddown with a 12% w/w aqueous solution of the gelatin (approx 150 mlsolution per kg of dry powder). The damped down mixture was then passedthrough an 8 mesh screen and dried at 60° C. for 2 hours, the dryproduct then being passed through a 20 mesh screen and blended with themagnesium stearate.

Compression

The core formulation may be compressed into a solid core and theintermediate and outer layers may be compressed around this core using asuitable rotary compression coating machine, e.g. a `Manesty`, `Drycota`or `Bicota` machine.

We claim:
 1. A pharmaceutical composition adapted for oesophagealadministration to a mammal comprising, as active ingredient, at leastone chromone compound selected from5-(2-hydroxypropoxy)-8-propyl-chromone-2-carboxylic acid;6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho-[2,3,-b]-pyran-2-carboxylicacid;6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3,-b]pyran-2-carboxylicacid or a pharmaceutically acceptable salt of any one thereof, incombination with an anti-inflammatory selected from aspirin,indomethacin, and mixtures thereof, said composition containing 0.004 to1200 parts by weight of said anti-inflammatory per part of said activeingredient.
 2. A composition according to claim 1, comprising from 24 to0.024 parts of aspirin for each part by weight (calculated as the sodiumsalt) of 5-(2-hydroxypropoxy)-8-propyl-chromone-2-carboxylic acid, or apharmaceutically acceptable salt thereof.
 3. A composition according toclaim 1, comprising from 4.0 to 0.004 parts by weight of indomethacinfor each part by weight (calculated as the sodium salt) of5-(2-hydroxypropoxy)-8-propyl-chromone-2-carboxylic acid, or apharmaceutically acceptable salt thereof.
 4. A composition according toclaim 1, comprising from 1200 to 0.3 parts by weight of aspirin for eachpart by weight (calculated as the sodium salt) of6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylicacid, or6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]-pyran-2-carboxylicacid, or a pharmaceutically acceptable salt of either thereof.
 5. Acomposition according to claim 1, comprising from 200 to 0.05 parts byweight of indomethacin for each part by weight (calculated as the sodiumsalt) of6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylicacid, or6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]-pyran-2-carboxylicacid, or a pharmaceutically acceptable salt of either thereof.
 6. Acomposition according to claim 1 comprising from 60 to 600 mg of aspirinin unit dosage form.
 7. A composition according to claim 1, comprisingfrom 10 to 100 mg of indomethacin in unit dosage form.
 8. A compositionaccording to claim 1, comprising from 25 mg to 2.5 g of5-(2-hydroxypropoxy)-8-propylchromone-2-carboxylic acid, or of apharmaceutically acceptable salt thereof, calculated as the sodium salt,in unit dosage form.
 9. A composition according to claim 1, comprisingfrom 0.5 to 200 mg of6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho-[2,3-b]-pyran-2-carboxylicacid, of6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]-pyran-2-carboxylicacid, or a pharmaceutically acceptable salt of either thereof,calculated as the sodium salt, in unit dosage form.
 10. A compositionaccording to claim 1 adapted to release some or all of the activeingredient first and to release the anti-inflammatory later.
 11. Apackage according to claim 1, wherein the unit doses are arranged in anorder which facilitates the administration to a mammal of a unit dose ofactive ingredient prior to or simultaneously with a unit dose of theanti-inflammatory.
 12. A pharmaceutical package comprising at least oneunit dose of the active ingredient of claim 1 and at least one unit doseof the anti-inflammatory of claim
 1. 13. A method of administering ananti-inflammatory to a mammal with inhibition of adversegastrointestinal effects due to said anti-inflammatory which methodcomprises orally administering to said mammal a composition according toclaim
 1. 14. A method of inhibiting adverse gastrointestinal effectscreated in a mammal by administration of an anti-inflammatory inaccordance with claim 1, which method comprises administering to saidmammal an active ingredient in accordance with claim 1, in theproportion of 0.004 to 1200 parts by weight of anti-inflammatory perpart of active ingredient, said active ingredient being administeredsequentially or substantially simultaneously with the administration ofsaid anti-inflammatory.